Abstract
Ischemic stroke (IS) poses a significant global health burden, with treatment efficacy often limited by the blood-brain barrier (BBB) and narrow therapeutic windows. Cell membrane-camouflaged biomimetic nanoparticles (CMC@NPs) represent an advanced drug delivery platform that integrates the versatility of synthetic nanocarriers with the biological functionality of natural cell membranes, thereby enhancing targeted delivery and immune evasion. However, a systematic assessment of their biosafety remains incomplete. This review critically evaluates both the safety profile and therapeutic efficacy of CMC@NPs in the context of IS, with a specific focus on the structure-activity relationships between their physicochemical properties and toxicological outcomes. We further explore their biosafety within the unique pathological microenvironment of IS. Key findings demonstrate that optimal particle size and surface functionalization critically determine biodistribution, enabling superior tissue penetration and prolonged circulation. Furthermore, naturally derived or engineered membrane proteins facilitate precise targeting to ischemic lesions, thereby enhancing drug accumulation and therapeutic efficacy. Concurrently, a mildly negative surface charge mitigates the risk of cerebral microvascular embolism, and targeted delivery significantly reduces systemic toxicity. The pivotal role of cell-specific uptake and clearance mechanisms in governing neurotoxicity and long-term accumulation is also emphasized. This review provides a foundational framework for the development of safer and more effective biomimetic nanomedicines for IS.